ml9b00586_si_001.pdf (7.47 MB)
Methyl Scanning and Revised Binding Mode of 2‑Pralidoxime, an Antidote for Nerve Agent Poisoning
journal contribution
posted on 2020-01-10, 16:38 authored by Adriana Gambino, James C. Burnett, Kazunori KoideOrganophosphorus
nerve agents (OPNAs) inhibit acetylcholinesterase (AChE) and, despite
the Chemical Weapons Convention arms control treaty, continue to represent
a threat to both military personnel and civilians. 2-Pralidoxime (2-PAM)
is currently the only therapeutic countermeasure approved by the United
States Food and Drug Administration for treating OPNA poisoning. However,
2-PAM is not centrally active due to its hydrophilicity and resulting
poor blood–brain barrier permeability; hence, these deficiencies
warrant the development of more hydrophobic analogs. Specifically,
gaps exist in previously published structure activity relationship
(SAR) studies for 2-PAM, thereby making it difficult to rationally
design novel analogs that are concomitantly more permeable and more
efficacious. In this study, we methodically performed a methyl scan
on the core pyridinium of 2-PAM to identify ring positions that could
tolerate both additional steric bulk and hydrophobicity. Subsequently,
SAR-guided molecular docking was used to rationalize hydropathically
feasible binding modes for 2-PAM and the reported derivatives. Overall,
the data presented herein provide new insights that may facilitate
the rational design of more efficacious 2-PAM analogs.